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Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms.

<div class='caption-title'>Pro-BMP9 and pro-BMP10 are equivalent ALK1-ligands.</div>
<div class='caption-title'>Crystal structure of human BMP10:ALK1 complex at 2.3 Å.</div>
<div class='caption-title'>Specificity determinants in the BMP9 and BMP10 subfamily.</div>
Salmon RM, Guo J, Wood JH, Tong Z, Beech JS, Lawera A, Yu M, Grainger DJ, Reckless J, Morrell NW, Li W
OpenAccess logo Nat Commun 11 1621 (2020)
Related entries: 6sf2, 6sf3

Cited: 44 times
EuropePMC logo PMID: 32238803

Abstract

Activin receptor-like kinase 1 (ALK1)-mediated endothelial cell signalling in response to bone morphogenetic protein 9 (BMP9) and BMP10 is of significant importance in cardiovascular disease and cancer. However, detailed molecular mechanisms of ALK1-mediated signalling remain unclear. Here, we report crystal structures of the BMP10:ALK1 complex at 2.3 Å and the prodomain-bound BMP9:ALK1 complex at 3.3 Å. Structural analyses reveal a tripartite recognition mechanism that defines BMP9 and BMP10 specificity for ALK1, and predict that crossveinless 2 is not an inhibitor of BMP9, which is confirmed by experimental evidence. Introduction of BMP10-specific residues into BMP9 yields BMP10-like ligands with diminished signalling activity in C2C12 cells, validating the tripartite mechanism. The loss of osteogenic signalling in C2C12 does not translate into non-osteogenic activity in vivo and BMP10 also induces bone-formation. Collectively, these data provide insight into ALK1-mediated BMP9 and BMP10 signalling, facilitating therapeutic targeting of this important pathway.

Articles - 6sf1 mentioned but not cited (4)

  1. Molecular basis of ALK1-mediated signalling by BMP9/BMP10 and their prodomain-bound forms. Salmon RM, Guo J, Wood JH, Tong Z, Beech JS, Lawera A, Yu M, Grainger DJ, Reckless J, Morrell NW, Li W. Nat Commun 11 1621 (2020)
  2. Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10. Guo J, Liu B, Thorikay M, Yu M, Li X, Tong Z, Salmon RM, Read RJ, Ten Dijke P, Morrell NW, Li W. Nat Commun 13 2395 (2022)
  3. Hereditary hemorrhagic telangiectasia: First demonstration of a founder effect in Italy; the ACVRL1 c.289_294del variant originated in the country of Bergamo 200 years ago. Sbalchiero A, Abu Hweij Y, Mazza T, Buscarini E, Scotti C, Pagella F, Manfredi G, Matti E, Spinozzi G, Olivieri C. Mol Genet Genomic Med 10 e1972 (2022)
  4. research-article AlphaFold2 enables accurate deorphanization of ligands to single-pass receptors. Danneskiold-Samsøe NB, Kavi D, Jude KM, Nissen SB, Wat LW, Coassolo L, Zhao M, Santana-Oikawa GA, Broido BB, Garcia KC, Svensson KJ. bioRxiv 2023.03.16.531341 (2023)


Reviews citing this publication (21)

  1. Influence of the TGF-β Superfamily on Osteoclasts/Osteoblasts Balance in Physiological and Pathological Bone Conditions. Jann J, Gascon S, Roux S, Faucheux N. Int J Mol Sci 21 E7597 (2020)
  2. Structural perspective of BMP ligands and signaling. Gipson GR, Goebel EJ, Hart KN, Kappes EC, Kattamuri C, McCoy JC, Thompson TB. Bone 140 115549 (2020)
  3. Hereditary Haemorrhagic Telangiectasia, an Inherited Vascular Disorder in Need of Improved Evidence-Based Pharmaceutical Interventions. Snodgrass RO, Chico TJA, Arthur HM. Genes (Basel) 12 174 (2021)
  4. The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease. Wu M, Wu S, Chen W, Li YP. Cell Res 34 101-123 (2024)
  5. Learning from BMPs and their biophysical extracellular matrix microenvironment for biomaterial design. Migliorini E, Guevara-Garcia A, Albiges-Rizo C, Picart C. Bone 141 115540 (2020)
  6. Pathophysiology and pathogenic mechanisms of pulmonary hypertension: role of membrane receptors, ion channels, and Ca2+ signaling. Balistrieri A, Makino A, Yuan JX. Physiol Rev 103 1827-1897 (2023)
  7. Molecular Mechanisms of AMH Signaling. Howard JA, Hart KN, Thompson TB. Front Endocrinol (Lausanne) 13 927824 (2022)
  8. An update on preclinical models of hereditary haemorrhagic telangiectasia: Insights into disease mechanisms. Arthur HM, Roman BL. Front Med (Lausanne) 9 973964 (2022)
  9. Peptides Derived from Growth Factors to Treat Alzheimer's Disease. Gascon S, Jann J, Langlois-Blais C, Plourde M, Lavoie C, Faucheux N. Int J Mol Sci 22 6071 (2021)
  10. Anti-Müllerian Hormone Signal Transduction involved in Müllerian Duct Regression. Cate RL. Front Endocrinol (Lausanne) 13 905324 (2022)
  11. An emerging class of new therapeutics targeting TGF, Activin, and BMP ligands in pulmonary arterial hypertension. Upton PD, Dunmore BJ, Li W, Morrell NW. Dev Dyn 252 327-342 (2023)
  12. Cancer and pulmonary hypertension: Learning lessons and real-life interplay. Pullamsetti SS, Nayakanti S, Chelladurai P, Mamazhakypov A, Mansouri S, Savai R, Seeger W. Glob Cardiol Sci Pract 2020 e202010 (2020)
  13. Emerging biologics for the treatment of pulmonary arterial hypertension. Hye T, Hossain MR, Saha D, Foyez T, Ahsan F. J Drug Target 31 1-15 (2023)
  14. The BMP Pathway in Blood Vessel and Lymphatic Vessel Biology. Ponomarev LC, Ksiazkiewicz J, Staring MW, Luttun A, Zwijsen A. Int J Mol Sci 22 6364 (2021)
  15. The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms. Butnariu LI, Gorduza EV, Florea L, Țarcă E, Moisă ȘM, Trandafir LM, Stoleriu S, Bădescu MC, Luca AC, Popa S, Radu I, Cojocaru E. Int J Mol Sci 23 12199 (2022)
  16. The potential regulatory role of BMP9 in inflammatory responses. Song T, Huang D, Song D. Genes Dis 9 1566-1578 (2022)
  17. The role of pro-domains in human growth factors and cytokines. Ratcliff M, Zhou RX, Jermutus L, Hyvönen M. Biochem Soc Trans 49 1963-1973 (2021)
  18. Genetics of brain arteriovenous malformations and cerebral cavernous malformations. Hongo H, Miyawaki S, Teranishi Y, Ishigami D, Ohara K, Sakai Y, Shimada D, Umekawa M, Koizumi S, Ono H, Nakatomi H, Saito N. J Hum Genet 68 157-167 (2023)
  19. Pathophysiology in Brain Arteriovenous Malformations: Focus on Endothelial Dysfunctions and Endothelial-to-Mesenchymal Transition. Jeong JY, Bafor AE, Freeman BH, Chen PR, Park ES, Kim E. Biomedicines 12 1795 (2024)
  20. Unveiling the Impact of BMP9 in Liver Diseases: Insights into Pathogenesis and Therapeutic Potential. Chen H, Li YY, Nio K, Tang H. Biomolecules 14 1013 (2024)
  21. [Research progress on bioinformatics in pulmonary arterial hypertension]. Peng W, Zhang ZY, Xiao YB. Zhongguo Dang Dai Er Ke Za Zhi 26 425-431 (2024)

Articles citing this publication (19)



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